Project Summary With 250 million infections and 500,000 deaths attributed to malaria each year, malaria is a significant burden on public health in the developing world. Of the five species of malaria that infect humans, Plasmodium vivax is the most globally widespread. The long-term objective of this study is to investigate the influence red cell physiology has on the survival of blood stage Plasmodium. The blood stage of P. vivax infection is responsible for all symptoms of disease, and is the reservoir from which the transmitted gametocyte stage emerges. Upon infecting a host red cell, P. vivax need the host red cell to remain in tact for the two days required for the parasite to produce the daughter merozoites that will initiate the next round of blood stage infection. A growing body of evidence suggests that the malaria parasites excessive digestion of host hemoglobin and new permeability pathways (NPPs) are responsible for maintaining the osmotic stability of the infected red cell. The impact host red cell physiology has on the osmotic stability of P. vivax infected red cells is not known. In this proposal, I will characterize the osmotic stability of uninfected and P. vivax infected nucleated red cell precursors and reticulocytes with small molecules (Aim 1), and I will identify red cell factors that determine premature hemolysis of P. vivax infected red cells with a forward genetic screen (Aim 2). The experiments proposed in this study have the potential to reveal a novel host antimalarial mechanism, therapeutic targets for the virulent blood stage of malaria infection, and may facilitate the adaptation of P. vivax to long term in vitro culture.